Molecular Entomology 2024, Vol.15, No.1, 18-22 http://emtoscipublisher.com/index.php/me 18 Scientific Commentary Open Access Analysis of the Mechanism of Action of Trametinib: Extending the Lifespan of Female Fruit Flies in Intestinal Stem Cells Henry Smith Molecular Entomology, EmtoSci Publisher, BC, V7A4Z5, Canada Corresponding author email: henry.smith@sophiapublisher.com Molecular Entomology, 2024, Vol.15, No.1 doi: 10.5376/me.2024.15.0003 Received: 19 Jan., 2024 Accepted: 01 Feb., 2024 Published: 10 Feb., 2024 Copyright © 2024 Smith, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Smith H., 2024, Analysis of the mechanism of action of trametinib: extending the lifespan of female fruit flies in intestinal stem cells, Molecular Entomology, 15(1): 18-22 (doi: 10.5376/me.2024.15.0003) "Trametinib ameliorates aging-associated gut pathology in Drosophila females by reducing Pol III activity in intestinal stem cells", Proceedings of National Academy of Sciences of the United States of America, January 19, 2024, by Enric Ureña, Bowen Xu, Jennifer C. Regan, Linda Partridge and others from the University of Washington, Friday Harbor, Washington, Biotechnology and Biological Sciences Research Council. In this study, the team explored the potential of the anticancer drug Trametinib to extend lifespan and improve gut health in fruit flies. The results showed that Trametinib significantly extended the lifespan and improved the gut health of female Drosophila by inhibiting RNA polymerase III (Pol III) activity in intestinal stem cells (ISCs). In contrast, the drug had a weaker lifespan extension and no significant improvement in gut health in male Drosophila. The study also found that Trametinib exerts its life-extending effects in ISCs in part through a Maf1-mediated mechanism. 1 Interpretation of Experimental Data In the present study, experimental data revealed the effects of Trametinib on intestinal stem cells (ISCs) and its potential mechanism for life extension through multiple perspectives. Trametinib showed a significant effect in reducing precursor tRNA synthesis, which was demonstrated by quantitative PCR (qPCR) techniques in whole Drosophila bodies, intestinal tissues, and specially isolated ISCs was confirmed. Survival curves revealed that Trametinib-fed Drosophila showed a significant increase in lifespan compared to controls. Additionally, the analysis revealed that Trametinib reduced the risk of intestinal barrier dysfunction and reduced epithelial dysplasia and tumor formation. Taken together, these data suggest that Trametinib reduces tRNA synthesis by inhibiting the Ras/MAPK signaling pathway and further inhibiting Pol III activity through Maf1, and that these molecular changes ultimately contribute to a healthy lifespan extension in Drosophila. This series of experimental data provides a solid molecular basis for the potential utility of Trametinib as an anti-aging drug. Figure 2 shows that Trametinib exhibited a significant effect in reducing the proliferation of intestinal stem cells (ISC) in 35-day-old female Drosophila, as measured by PH3+ staining showed that there were fewer mitotic cells in the Trametinib group compared to the DMSO control group, suggesting that it effectively inhibited ISC proliferation. The effect of Trametinib in male Drosophila was weaker than that in female, but still statistically significant.The microscopic images and their analysis in part B revealed that Trametinib treatment significantly reduced the irregular proliferation of intestinal epithelium in female Drosophila, which was not found in male Drosophila.In part C, the intestinal barrier function of the Trametinib-treated females was improved and reduced in the Trametinib-treated female Drosophila at 60 days of age, and the decline of intestinal barrier function was improved and reduced. In part C, Trametinib-treated female Drosophila ameliorated the decline in intestinal barrier function at 60 days of age, reducing the proportion of "smurf" Drosophila, whereas this change was not apparent in male Drosophila. These results indicate the potential benefit of Trametinib in improving intestinal health and functional decline in female Drosophila.
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